Summary

The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) clinical recommendation group has published guidelines for the use of CYP2D6 genotype when prescribing codeine. They recommend that poor metabolizers of CYP2D6 should not receive codeine for pain relief, and ultrametabolizers of CYP2D6 should avoid codeine for pain relief.

Summary

PharmGKB annotates drug labels containing pharmacogenetic information approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency, Japan (PMDA). PharmGKB annotations provide a brief summary of the PGx in the label, an excerpt from the label and a downloadable highlighted label PDF file. A list of genes and phenotypes found within the label is mapped to label section headers and listed at the end of each annotation. PharmGKB also attempts to interpret the level of action implied in each label with the "PGx Level" tag.

Sources:

FDA Information is gathered from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" and from FDA-approved labels brought to our attention. Please note that drugs may be removed from or added to the FDA's Table without our knowledge. We periodically check the Table for changes and update PharmGKB accordingly. Drugs listed on the Table to our knowledge are tagged with the Biomarker icon. A drug label that has been removed from the Table will not have the Biomarker icon but will continue to have an annotation on PharmGKB stating the label has been removed from the FDA's Table. We acquire label PDF files from DailyMed.

EMA European Public Assessment Reports (EPARs) that contain PGx information were identified from [Article:24433361] and also by searching for drugs for which we have PGx-containing FDA drug labels.

Summary

CYP2D6 ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing at normal dosing regimens. Mothers who are ultra-rapid metabolizers and breast-feeding have higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants, potentially leading to serious adverse reactions, including death, in nursing infants. A black box warning on the label states "Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism." However, no recommendations for testing for CYP2D6 metabolizer status are provided on the label.

Annotation

Codeine is an opiod analgesic pro-drug, typically used for pain relief. It is metabolized by CYP2D6 into morphine, which is the active drug form. CYP2D6 poor and ultra-rapid metabolizers may experience different efficacy. Mothers who are ultra-rapid metabolizers and breast-feeding should be particularly aware of potential danger to breastfed infants. The FDA added a boxed warning to the label for children who receive codeine following tonsillectomy and/or adenoidectomy who may be CYP2D6 rapid metabolizers, and codeine in contraindicated in this patient population.

Excerpts from the codeine sulfate drug label:

Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.

Codeine is secreted into human milk...some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

Disclaimer:
The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed
literature available at the time they are written and are intended only to assist clinicians in decision-making
and to identify questions for further research. New evidence may have emerged since the time an annotation was
submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or
diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all
proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider
to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the
ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB
assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of
the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the
"Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the
corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated
information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications
can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding
Variant Page.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

Source: Drug Bank

Pharmacology

Codeine, an opiate agonist in the CNS, is similar to other phenanthrene derivatives such as morphine. Codeine, in combination with guaifenesin or iodinated glycerol, is used as a cough suppressant and, as a single agent or in combination with acetaminophen or other products, is used for pain control and as an antidiarrheal agent.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic. Codeine is a prodrug, itself inactive, but demethylated to the active morphine by the liver enzyme CYP2D6.

Source: Drug Bank

Protein Binding

7-25%

Source: Drug Bank

Absorption

Well absorbed following oral administration with a bioavailability of approximately 90%.

Source: Drug Bank

Half-Life

2-4 hours

Source: Drug Bank

Toxicity

Respiratory depression, sedation and miosis and common symptoms of overdose. Other symptoms include nausea, vomiting, skeletal muscle flaccidity, bradycardia, hypotension, and cool, clammy skin. Apnea and death may ensue.

Source: Drug Bank

Chemical Properties

Chemical Formula

C18H21NO3

Source: Drug Bank

Isomeric SMILES

CN1CC[C@]23c4c5ccc(c4O[C@H]2[C@H](C=C[C@H]3[C@H]1C5)O)OC

Source: OpenEye

Canonical SMILES

COC1=C2O[C@H]3[C@@H]

Source: Drug Bank

Average Molecular Weight

299.3642

Source: Drug Bank

Monoisotopic Molecular Weight

299.152143543

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2)
literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on
the "evidence" and "source" listed below.